The principal goal of this research is the design and synthesis of structurally diverse, orally bioavailable HIV-1 protease inhibitors based on 3,5- and 2,5-linked pyrrolinones. Related objectives include: (i) further elucidation of the solution and solid-state conformations of the pyrrolinones; (ii) generalization of the synthetic protocols to accommodate side-chains of both coded and uncoded amino acids; (iii) development of solid-phase syntheses to facilitate library construction; and (iv) inhibition of other biomedically important proteases, demonstrating that the chosen scaffolds are useful platforms.